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To further assist applicants in preparing complete and high quality Product Licence Applications (PLAs) for traditional claim submissions, the Natural Health Products Directorate (NHPD) has developed an Evidence Criteria and Evidence Assessment Template for this application type (i.e. traditional claim).
Both the Criteria and the Template are to be used by applicants to ensure that the evidence portions of their PLAs for traditional claim submissions are not critically deficient and meet a minimum level of quality.
The Evidence Criteria were developed based on a number of critical evidence deficiencies the NHPD has frequently encountered since it began assessing PLAs in January 2004. PLAs for traditional claim submissions without any of the evidence deficiencies will remain in queue for a comprehensive assessment of the product's safety, efficacy and quality. For submissions with critical deficiencies, applicants will be issued an Evidence Information Request Notice (E-IRN) outlining the deficiencies.
Upon receipt of the E-IRN, applicants will have thirty days to respond to the deficiencies or to withdraw their application. Applicants that do not provide a satisfactory response addressing all deficiencies within thirty days will be issued a notice of refusal for the submission.
Prior to submitting their PLAs for traditional claim submissions or responses to E-IRNs, applicants are strongly encouraged to cross check their supporting evidence against the Evidence Criteria and to use the Evidence Assessment Template (both provided in this notice) to ensure that the evidence they intend to submit is relevant and complete.
Applicants should note that PLAs for traditional claim submissions are not being subjected to new evidence requirements. The NHPD is simply modernizing its assessment process to ensure that PLAs with critically deficient evidence are identified at the outset and are addressed quickly rather than allowing them to sit in the assessment queue for lengthy periods of time without progress. The NHPD will continue to thoroughly assess all PLAs to ensure that the evidence provided is appropriate for the product.
Streamlining the IRN process will enable the NHPD to focus its assessment resources and expertise on higher quality submissions and ensure a more timely and efficient review of submissions. Furthermore, with the Evidence Assessment Template in hand, applicants now have an easy-to-use tool to ensure that their PLAs for traditional claim submissions meet the most fundamental evidence requirements.
The Evidence for Safety and Efficacy of Finished Natural Health Products guidance document provides detailed information on the NHPD's evidence requirements. Applicants are encouraged to read, understand and follow this document as it provides essential guidance on the safety and efficacy requirements for traditional claim applications.
The NHPD has observed that in the vast majority of cases, the severely deficient PLAs received for traditional claim submissions are the result of applicants not properly crosschecking their PLA information against the NHPD's evidence requirements prior to submitting. Applicants should attain a working knowledge of the Evidence for Safety and Efficacy of Finished Natural Health Products guidance document and use the developed Criteria and Assessment Template to ensure that the evidence portions of their PLAs for traditional claim submissions are not critically deficient.
The NHPD anticipates that this modernized approach will significantly strengthen the efficiency and timeliness of the review process, enabling applicants who have submitted complete and high quality PLAs for traditional claim submissions to have their application assessed within a reasonable and acceptable timeline.
Should you have any questions or concerns, please do not hesitate to contact your Submission Coordinator.
The Evidence Criteria were developed based on a number of critical evidence deficiencies the Natural Health Products Directorate (NHPD) has frequently encountered since it began assessing Product Licence Applications (PLAs) for traditional claim submissions in January 2004. Upon entry into the assessment level, the NHPD is now immediately screening submissions against the Criteria to ensure that the evidence provided is not critically deficient and meets a minimum level of quality.
Prior to submitting their PLAs for traditional claim submissions, applicants are strongly encouraged to cross check their supporting evidence against the Evidence Criteria below.
1) Evidence has not been provided/The Evidence provided is not considered sufficient/to support the traditional use of the medicinal ingredient(s) [XXX and YYY].
2) Evidence has not been provided/The Evidence provided is not considered sufficient/to support the use of the medicinal ingredient(s) [XXX and YYY] within the same identified traditional healing paradigm [ZZZ].
3) The product and/or the medicinal ingredient(s) [XXX and YYY] on the PLA form is/are not comparable to the product and/or medicinal ingredient(s) discussed in the evidence (Insert reference(s)).
NOTE: Authoritative references on Traditional Chinese Medicine (TCM), unless otherwise specified, provide dosage information for individual medicinal ingredients as a decoction and are not comparable to ethanol-based preparations or non-extracted powders.
4) Evidence provided is not considered adequate to support the safety of the product and/or the medicinal ingredient(s) [XXX and YYY] [within the subpopulation [ZZZ]].
The safety of a product with a traditional claim must be established based on both references about its traditional use and the scientific literature. Should the available scientific evidence suggest that the medicinal ingredient is unsafe when used according to the product's recommended conditions of use, a higher level of scientific evidence must be provided and the totality of evidence must demonstrate the contrary.
NOTE: For medicinal ingredients that are not comparable (as in criterion 3), it would be generally understood, due to the gaps in the evidence, that evidence in support of their safety may also be lacking.
5) The phrase(s)/term(s) ["XXX" and "YYY"] as part of the recommended use or purpose/The recommended use or purpose "XXX" is/are not acceptable as it/they relate(s) to:
A serious disease, condition, abnormal physical state or Schedule A disease.
Examples of terms/phases that would be deemed inappropriate as a traditional claim include references to:
A condition that cannot be diagnosed within the identified healing paradigm.
Examples of recommended uses or purposes falling into this category would include the following:
A specific pharmacological effect which must be substantiated based on scientific evidence.
Examples of recommended uses or purposes or terms that would have a meaning so specific to require scientific evidence and thus would be inappropriate as a traditional use claim would include:
Broad/vague symptoms and/or actions which do not specify any meaningful or beneficial effect of the product.
Examples of these types of claims would include:
Sexual desire, fertility, libido, impotence, etc.
The standards of evidence used to support traditional use claims are not suited for these types of claims. Hence, products intending to make claims of this nature must adhere to the requirements in place for non-traditional applications.
An interpretation/extrapolation of available evidence on the respective medicinal ingredient(s) to support a claim which is not in fact a traditional use.
This deficiency often results from inaccurate interpretation and/or extrapolation of traditional evidence or representation of information based on scientific investigations of a medicinal ingredient as traditional.
Examples include addiction cessation claims, weight loss claims and source of vitamin, essential fatty acids and/or minerals, etc claims.
6) Information on the dose of the medicinal ingredient(s) [XXX and YYY] [used topically/when applied externally] is missing or incomplete within the evidence submitted (Insert reference(s)).
7) Evidence submitted for the medicinal ingredient(s) [XXX and YYY] pertains to a different route of administration than that indicated in the recommended conditions of use section of the PLA (Insert reference(s)).
The evidence provided for the medicinal ingredient(s) is based on oral use, but the product is used topically.
8) The daily doses indicated on the PLA form for each of the medicinal ingredients listed are below the dosage range indicated in the submitted evidence and there is no basis to conclude [all or a subset] of the medicinal ingredients are additive.
NOTE: When the daily dose of each medicinal ingredient is below that supported by the literature, it would not be possible for the recommended dose of the product to be supported unless two or more of the medicinal ingredients in the product are considered additive (based on the submitted evidence) and accompanied by an Additive Combinations Evaluation (ACE) form which adheres to the 80-120% rule. Appendix 1 should be consulted for more detailed information on considerations for multi-medicinal ingredient products including how to complete and support the information within an ACE form.
9) A combination rationale has not been provided for this product [including a product monograph in support of the base formula - (applicable to TCM formulas)]/The submitted combination rationale is insufficient/unacceptable based on the submitted evidence.
For all products consisting of two or more medicinal ingredients, where the product formulation with respect to its traditional use cannot be supported on the basis of a single product monograph (e.g. Pharmacopoeia of the People's Republic of China, the State Drug Standard or the Ayurvedic Pharmacopoeia of India), the product formulation is to be based on combining medicinal ingredients that are logical and permissible (based on their respective uses within the same identified healing paradigm). The combination rationale should clearly indicate which medicinal ingredients are complementary, additive or antagonistic.
NOTE: For a product with a claim drawn from the Traditional Chinese Medicine (TCM) paradigm, unless the formulation is captured in a suitable stand-alone reference and the corresponding reference has been provided, the combination rationale must explain the respective role (e.g. king, minister, assistant and messenger) of each medicinal ingredient in the formulation, contribution to the overall efficacy of the product and the traditional formula used as the basis for the combination must be provided. Furthermore, the combination rationale should speak to any deviations from the base formula and how the noted deviation(s) do or do not impact the efficacy/claim and safety of the formulation.
Only solicited changes are permitted during the assessment phase. Applicants must ensure that any revisions made to the PLA form and label are in accordance with the requirements outlined in the Evidence for Safety and Efficacy of Finished Natural Health Products guidance document for a Traditional Medicine and supported by the submitted evidence.
Applicants may request a reclassification of the application type, but must ensure that their application conforms fully to the requirements of the new application stream.
A combination rationale is required for all multi-medicinal ingredient products (i.e. two or more medicinal ingredients in a single product), unless all of the medicinal ingredients of the product are captured in a single product monograph. At a minimum, the single product monograph must identify the respective dose for each medicinal ingredient and the recommended use or purpose for the product.
Thus, in the absence of a single product monograph that captures the product in its entirety, the combination rationale speaks to the following:
The combination rationale plays a pivotal part in positioning the role of each medicinal ingredient within the context of the product claim and associated conditions of use and should be in agreement with the submitted evidence. There is no particular format as to what a combination rationale should look like, however it is intended to present an objective answer as to why each medicinal ingredient is present and the contribution of each medicinal ingredient to the overall efficacy and safety of the product. Consequently, such an answer must be founded on the submitted evidence.
Suppose a product consists of medicinal ingredients X, Y and Z, where their respective uses based on the submitted evidence are as follows:
Based on the submitted evidence, it would be acceptable to indicate that the medicinal ingredients X, Y, Z are all used within traditional herbal medicine for their sedative properties and the combination of the medicinal ingredients is amenable to the product's recommended use or purpose of "Traditionally used in Herbal Medicine for the relief of restlessness".
Note: Traditional Chinese Medicine formulations are based on a hierarchical system of function which establishes the respective role (e.g. king, minister, assistant and messenger) of each medicinal ingredient in the formulation. Therefore the combination rationale for a TCM product must explain the role of each medicinal ingredient based on this hierarchical system.
Consider Er chen tang, a formula used for removing dampness and phlegm, typically consists of Citrus reticulata, Pinellia ternata, Poria cocos, Glycyrrhiza uralensis and in some cases Zingiber officinale.
Suppose Er chen tang is provided as the base formula, but the product represented on the PLA has Scutellaria baicalensis in place of Pinellia ternata. At a minimum, the combination rationale must to explain why this substitution would be acceptable based on the theory of Traditional Chinese Medicine. Part of the rationale would be to demonstrate the interchangeability of Scutellaria baicalensis and Pinellia ternata by considering their properties (e.g. warm, cold, etc), channels entered (e.g. lung, spleen, liver, etc) and action (e.g. relief of Qi stagnation, clears heat, removes dampness, etc) as described in the submitted evidence. In order, for medicinal ingredients to be considered interchangeable, their properties, channels entered and actions must be alike.
An Additive Combinations Evaluation (ACE) form is a table that lists the medicinal ingredient of a product that are regarded as additive (i.e. can be used for the same recommended use or purpose). To use the earlier example of a product consisting of medicinal ingredients X, Y and Z, where each medicinal ingredient is used within traditional herbal medicine for its sedative properties, it would be possible to support a claim of "Traditionally used in Herbal Medicine for the relief of restlessness" for a single medicinal ingredient product consisting of either X, Y or Z. This is an important factor in distinguishing whether the medicinal ingredients listed on an ACE form are indeed additive, because the concept of additive medicinal ingredients is predicated on the idea that any of the medicinal ingredients considered to be additive, is capable of meeting the claim (for which it is additive) independently, provided that the respective dose for that ingredient is adjusted accordingly.
To introduce a new example, suppose a product consists of medicinal ingredients A, B, C, D and E where the product dose of each medicinal ingredient is 400 mg/day and the submitted evidence supports each of the medicinal ingredients as having been used singly at 1000 mg/day in Traditional Herbal Medicine (THM) for the following:
There are a number of medicinal ingredients that could be considered additive, the most obvious being B and D. Now, if the recommended use or purpose for the product is "Used in Traditional Herbal Medicine to aid in the relief of feverish colds and cough", medicinal ingredients B, D and E could be considered as additive for "the relief of feverish colds" component of the claim. Medicinal ingredients B, C and D could be regarded as additive for the "cough" component of the claim.
Consequently, if the product claim is as described above, it would be most appropriate to submit two ACE forms, one for medicinal ingredients B, D and E and the other for medicinal ingredients B, C and D as a means of demonstrating that the sub-therapeutic doses (i.e. 400 mg/day) of the respective medicinal ingredients amounts to a full therapeutic dose based on a subset of the medicinal ingredients of the product being considered additive.
NOTE: Medicinal ingredients are considered additive if the submitted evidence establishes each of the respective medicinal ingredients as alleviating the same symptom (e.g. fever associated with a cold). If the submitted evidence established the respective medicinal ingredients as alleviating different symptoms (e.g. sore throat vs. expectorant) of the same health condition (e.g. cold), the medicinal ingredients would be complementary.
An ACE form comprises of several important fields, each of which are explained.
A completed ACE form should include only the medicinal ingredients that can be considered as addressing the same symptom of a particular health condition. If the recommended use or purpose of the product identifies multiple symptoms and/or health conditions, then multiple ACE forms should be submitted. Doses reported on the ACE form must be expressed in terms of the quantity crude equivalent (QCE) for extracted medicinal ingredients.
Provided is an example of an appropriately completed ACE form, based on three medicinal ingredients (Matricaria recutita flowers, Humulus lupulus strobiles, Passiflora incarnata flowers) that can be regarded as additive based on the submitted evidence.
|Additive Indication:||Traditionally used in herbal medicine as a sedative for restlessness.|
|Recommended Dose:||2 tablets at bedtime|
|Medicinal Ingredient, Source, Single Ingredient Daily Reference Dose Range||Min. Daily Ref. Dose (mg/day)||Max. Daily Ref.Dose (mg/day)||Weight Per Dosage Unit (mg)||Recommend. Product Daily Dose (mg/day)||% Min Daily Ref. Dose||% Max Daily Ref. Dose|
|Passiflora incarnata Dried flowers 250-1000 mg 3x/dayFootnote 1||750||3000||300||2 x 300 = 600||600 / 750 = 80%||600 / 3000 = 20%|
|Humulus lupulus Dried strobiles 500-1000 mg/dayFootnote 1||500||1000||150||2 x 150 = 300||300 / 500 = 60%||300 / 1000 = 30%|
|Matricaria recutita Dried flowers 2000-8000 mg 3x/dayFootnote 1||6000||24000||500||2 x 500 = 1000||1000 / 6000 = 17%||1000 / 24000 = 4%|
|Sum of Percentages:||157%||54%|
NOTE: At the product's recommended dose, the Percent Minimum Daily Reference Dose must be equal to or greater than 80% and represents efficacy, whereas the Percent Maximum Daily Reference Dose must be equal to or less than 120% and represents safety. Thus, the all completed ACE forms must conform to the 80% to 120% rule.
The Evidence Assessment Template is a tool developed to help applicants in the review of the evidence and to ensure that the evidence they intend to submit as part of the Product Licence Application (PLA) for traditional claim submissions is complete and adequately supports the safety and efficacy of the natural health product for which a licence is being sought.
Applicants should use this template in conjunction with the Evidence Criteria.
|1. Sufficient evidence has been provided to support the traditional use of EACH medicinal ingredient of the product.|
|2. Sufficient evidence has been provided to support the traditional use of EACH medicinal ingredient of the product within the same identified traditional healing paradigm.|
|3. EACH medicinal ingredient of the product (as identified on the PLA form) is comparable to medicinal ingredient captured in the evidence.|
|4. Evidence provided is adequate to support safety of EACH medicinal ingredient of the product within all of the indicated subpopulations.|
|5. The recommended use or purpose does not include reference to:
|6. Evidence includes complete information on the dose traditionally used for EACH medicinal ingredient of the product.|
|7. Evidence submitted for EACH medicinal ingredient of the product pertains to the same route of administration indicated on the PLA form.|
|8. The daily doses indicated on the PLA form for one or more of the medicinal ingredient(s) is within the dosage range captured in the evidence or an Additive Combinations Evaluation (ACE) form is provided.|
|9. A combination rationale is provided and explains the role of EACH medicinal ingredient of the product within the same identified traditional healing paradigm.|